Process for the production of triiodotrimesic acid

ABSTRACT

A new process for the production of triiodotrimesic acid that is used as an intermediate product for the synthesis of x-ray contrast media is described.

This application claims the benefit of the filing date of U.S.Provisional Application Ser. No. 60/487,976 filed Jul. 18, 2003, whichis incorporated by reference herein.

Triiodotrimesic acid (formula I) is an important intermediate productfor the production of nonionic triiodized x-ray contrast media. Thus,the production of tris-amides of triiodotrimesic acid is described in,for example, DE 3001292 (Schering). Such compounds are especiallyadvantageous because of their favorable pharmacological properties.Attempts to make economic use of these tris-amides have failed because,up until now, no commercially usable way has been found to access theactual starting compound, the triiodotrimesic acid. Further developmentof a contrast medium with especially good properties, iosimide, whichwas already in phase In of the clinical examinations, was unsuccessfuldue to the high production costs of the triiodotrimesic acid.

Thus, in DE 2831496, the production of the triiodotrimesic acid,starting from nitroisophthalic acid, is described:

In this process, nitroisophthalic acid is hydrogenated to form an aminocompound and then iodized with chloroiodine. The introduction of themissing carboxyl group can be accomplished with a Sandmeyer reaction(HNO₂/KCN/CuCN). This reaction step proved very critical especially inincreasing coarseness of the batch, since, on the one hand, hydrogencyanide is produced, and in addition the copper ions must be used inexcess. The removal of copper wastes from the reaction water can beconsidered especially critical on an industrial scale. A critical stepis also the complete saponification of nitrile to carboxylic acid. Inthis connection, the process has to pass through an intermediate stage,the amide, which proved very difficult to hydrolyze.

In another patent (NYCOMED: U.S. Pat. No. 5,882,628), intermediatestages are described that were considered as starting products for thesynthesis of triiodotrimesic acid:

Triiodomesitylene is converted under acetylating conditions in anoxidation reaction with potassium permanganate/acetic anhydride/aceticacid/sulfuiric acid into triacetate (yield: 35%). The triacetate isisolated and saponified with potassium carbonate in methanol to trisalcohol (yield: 94%). The tris alcohol is then reacted to form trisaldehyde by Swem oxidation in dimethyl sulfoxide as a solvent in a yieldof 67%.

Additional oxidation to tricarboxylic acid was not described in thispatent and also is not reported with this step in literature.

There was therefore the need for a new synthesis that providestriiodotrimesic acid in a higher total yield from advantageousenvironmental and safety standpoints and that also has the capacity forincreasing coarseness of the batch. These requirements are, surprisinglyenough, met by the new two-stage synthesis that is present here. Thefollowing synthesis diagram shows the new method of synthesis thatstarts from triiodomesitylene:

In this connection, starting from triiodomesitylene, the reaction isperformed with potassium or sodium permanganate in a mixture thatconsists of acetic acid anhydride, acetic acid and sulfuric acid in avolume ratio of 15-30:10-20:1.25-3.5, preferably 20:15:2.5. The sulfuricacid is used at the concentration of 70%-100%, preferably 95-100%. Thereaction is carried out at temperatures of 10 to 120° C., preferably20-100° C., especially preferably 40-80° C. The reaction period is 12-36hours, preferably 15-25 hours.

Then, it is distilled off. This can be carried out directly from thebatch, whereby the pressure optionally is reduced. In this case, amixture that consists of acetic acid and acetic anhydride is obtained.Also, however, only water can be added to destroy excess acetic acidanhydride, and then pure acetic acid is distilled off. The recoveredacetic acid can be reused.

Then, the sulfuric acid is neutralized in the residue by adding aninorganic base such as sodium hydroxide solution, potassium hydroxidesolution, or calcium hydroxide in solid form, or, preferably, as anaqueous solution, and the concentration by evaporation is continued.

After concentration by evaporation is completed, water is added attemperatures of between 60-100° C., then it is absorptivelyprecipitated, and the precipitated1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene (II) is filteredoff, which is washed with water and methanol and then dried.

In the next reaction step, the1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene (II) is introducedinto water at temperatures of 60-100° C., preferably 80-100° C. (reflux)and mixed with an aqueous solution of an inorganic base, preferablysodium hydroxide solution, potassium hydroxide solution, calciumhydroxide, sodium carbonate or potassium carbonate, but especiallypreferably NaOH or KOH. The period of dropwise addition of the base is30 minutes to 10 hours, preferably 30 minutes to 3 hours. Then, it isstirred for 1 to 24 hours, preferably 3-12 hours, especially preferably4-8 hours, at temperatures of between 60 and 100° C., especiallypreferably 80-100° C. Then, it is neutralized with an inorganic acid(pH=6-7), preferably hydrochloric acid, hydrobromic acid or sulfuricacid, but especially preferably concentrated hydrochloric acid;magnesium sulfate is added to the hot reaction solution, and an aqueouspotassium or sodium permanganate solution is added in drops and thenstirred for 1 to 24 hours, preferably 1-12 hours, especially preferably2-4 hours at temperatures of between 60 and 100° C., especiallypreferably 80-100° C.

The subsequent working-up can be carried out in different ways:

1. Excess oxidizing agent can be destroyed by adding a reducing agent insolid or dissolved form (aqueous solution). For this purpose, inparticular inorganic sulfites or hydrogen sulfites, such as sodiumsulfite/hydrogen sulfite or potassium sulfite/hydrogen sulfite,especially preferably sodium sulfite or lower alcohols such as methanol,ethanol, isopropanol, and glycol are suitable. The latter takes place attemperatures of between 10 to 100° C., preferably 20-80° C. Then, a pHof 0.1-3, preferably 0.5-1, is set by adding sulfuric acid, and theproduct is extracted by extraction with an organic solvent, such asethyl acetate, propyl acetate, methyl-butyl ether (MTB), tetrahydrofuran(THF), n-butanol, methyl-THF, dichloromethane, or toluene. Ethyl acetateand MTB are preferred. The organic phases can optionally be washed withwater, brine or acidified water and are evaporated to the dry state. Ithas proven especially advantageous to redistill directly the solventthat is used for crystallization. In this case, the first solvent isreplaced by the second solvent during the distillation by continuousaddition of a second solvent. As a solvent for crystallization,especially cyclohexane and n-heptane, as well as their mixtures withethyl acetate, toluene and MTB, have proven their value.

In many cases, an extraction with an organic solvent, as describedabove, can also be eliminated. To this end, it is largely evaporated tothe dry state under reduced pressure, and then water is largely removedby adding an azeotrope-forming solvent such as methanol, ethanol,isopropanol, dichloromethane, MTB, ethyl acetate, butyl acetate,butanol, toluene or THF. The amount of residual water is determined byKarl-Fischer (KF) titration. Then, the remaining residue is absorptivelyprecipitated with an organic solvent, such as methanol, ethanol,isopropanol, dichloromethane, MTB, ethyl acetate, butyl acetate,butanol, toluene or THF at temperatures of between 20-100° C., and saltsare filtered out. The filtrate can be evaporated to the dry state orelse, as described above, a solvent that is suitable for crystallizationcan be redistilled.

2. In many cases, it has proven advantageous not to add any reducingagent but rather to set the pH to 0.1-3, but preferably 0.1-1, by addingsulfuric acid and then to evaporate it to the dry state as describedabove under reduced pressure and to absorptively precipitate the residuewith an organic solvent (analogous procedure to that under 1).

The synthesis process that is described here is characterized by severalimportant advantages compared to the process of the prior art:

The inexpensive and nontoxic potassium or sodium permanganate is used asthe only oxidizing agent. The manganese wastes that are produced can bemade reusable in a recycling process by further oxidation.

The process is robust and can easily be implemented on a multi-tonscale. It is distinguished by an environmentally sound solvent. Theprocess is inexpensive in implementation, consists of only two stagesand provides a high total yield of 80-85% of theory.

This process thus represents a valuable contribution to the productionof an intermediate stage of the triiodized tris-amides that areimportant for medical diagnosis.

The examples below are used to describe the new process:

Production of Triiodotrimesitylene

Carried out according to Synthesis 6, 486 (1980); WO 96/09282, J. Med.Chem. (2000) 43 (10), 1940 or according to Synlett (2002), (4), 598

Production of 1,3,5-Triiodo-2,4-diacetoxymethylene-6-methylbenzene (II)

400 g (803 mmol) of triiodomesitylene is suspended in 0.9 l of aceticanhydride, 1.4 l of acetic acid and 121 ml of concentrated sulfuricacid, and 160 g (1.01 mol) of potassium permanganate is added inportions (over 2 hours) at 40° C. and stirred for 18 hours at 40° C.After the reaction is completed, 152 ml of water is carefully addedwhile being stirred, and stirring is continued for 2 hours at roomtemperature. Then, 363.2 ml of 50% sodium hydroxide solution (exactlythe amount to neutralize the sulfuric acid!) is added. Then, it islargely distilled off (concentrated by evaporation) under reducedpressure. 4 l of water is added in drops while being stirred, and it isthen stirred for one hour at 10° C. The deposited precipitate issuctioned off, rewashed twice with 1.5 l of water each and with 500 mlof methanol, and it is dried in a vacuum at 50° C.

Yield: 0.456 kg (93% of theory)

Elementary analysis: Cld.: C 24.43 H 2.13 J 62.01 Fnd.: C 24.26 H 2.09 J62.31Production of Triiodotrimesic Acid (I) (Variant A)

250 g (407 mmol) of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzeneis suspended in 2.5 l of water and mixed carefully at 90° C. with 200 mlof 50% sodium hydroxide solution and stirred for 5 hours at 90° C. Then,it is neutralized with concentrated hydrochloric acid (pH=6-7), mixedwith 367 g (1.488 mol) of magnesium sulfate, a solution that consists of411 g (2.604 mol) of potassium permanganate in 4 l of water is added indrops, and it is stirred for 2 hours under reflux. It is cooled to roomtemperature (RT), 50 g of sodium sulfite is added, and it is stirred forone hour at room temperature. Then, it is set at a pH of 1 with 50%sulfuric acid. 2 l of ethyl acetate is added, and it is thoroughlystirred. The organic phase is separated, and the aqueous phase issubsequently re-extracted 2× with 0.5 l of ethyl acetate. The organicphases are combined, rewashed once with 2.5 l of water and thenredistilled with cyclohexane. During cooling (0° C.), the productcrystallizes out.

Yield: 206 g (86% of theory)

Elementary analysis: Cld.: C 18.39 H 0.51 J 64.77 Fnd.: C 18.47 H 0.56 J64.65Production of Triiodotrimesic Acid (I) (Variant B)

250 g (407 mmol) of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzeneis suspended in 2.5 l of water and mixed carefully at 90° C. with 200 mlof 50% sodium hydroxide solution and stirred for 5 hours at 90° C. Then,it is neutralized with concentrated hydrochloric acid (pH=6-7), mixedwith 367 g (1.488 mol) of magnesium sulfate, a solution that consists of411 g (2.604 mol) of potassium permanganate in 4 l of water is added indrops, and it is stirred for 2 hours under reflux. It is cooled to roomtemperature (RT), 50 g of sodium sulfite is added, and it is stirred forone hour at room temperature. Then, it is set at a pH of 1 with 50%sulfuric acid. 2 l of ethyl acetate is added, and it is thoroughlystirred. The organic phase is separated, and the aqueous phase issubsequently re-extracted 2× with 0.5 l of ethyl acetate. The organicphases are combined and rewashed once with 2.5 l of water. The ethylacetate solution is distilled off to remove water azeotropically (watercontent according to Karl-Fischer titration <0.2%). A thus producedsolution can be used for further reaction (e.g., production of acidchloride with SOCl₂). By concentration by evaporation of an aliquot, theyield was determined.

Yield: 211 g (88% of theory)

Elementary analysis: Cld.: C 18.39 H 0.51 J 64.77 Fnd.: C 18.50 H 0.62 J64.54Production of Triiodotrimesic Acid (I) (Variant C)

250 g (407 mmol) of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzeneis suspended in 2.5 l of water and mixed carefully at 90° C. with 200 mlof 50% sodium hydroxide solution, and it is stirred for 5 hours at 90°C. Then, it is neutralized with concentrated hydrochloric acid (pH=6-7),mixed with 367 g (1.488 mol) of magnesium sulfate, a solution thatconsists of 411 g (2.604 mol) of potassium permanganate in 4 l of wateris added in drops, and it is stirred for 2 hours under reflux. It iscooled to room temperature (RT), 50 g of sodium sulfite is added, and itis stirred for one hour at room temperature. Then, it is set at a pH of1 with 50% sulfuric acid. It is largely concentrated by evaporation in avacuum, and residual water is distilled off azeotropically by addingisopropanol. The isopropanol is continuously added. At a water content<1% (KF titration), another 10 l of isopropanol is added, and it isstirred for one hour at 40° C. Filtration is done from salt paste, andit is flushed two more times with 3 l of isopropanol. The filtrate isevaporated to the dry state in a vacuum.

Yield: 213 g (89% of theory)

Elementary analysis: Cld.: C 18.39 H 0.51 J 64.77 Fnd.: C 18.46 H 0.59 J64.64Production of Triiodotrimesic Acid (D) (Variant D)

250 g (407 mmol) of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzeneis suspended in 2.5 l of water and mixed carefully at 90° C. with 200 mlof 50% sodium hydroxide solution and stirred for 5 hours at 90° C. Then,it is neutralized with concentrated hydrochloric acid (pH=6-7), mixedwith 367 g (1.488 mol) of magnesium sulfate, a solution that consists of411 g (2.604 mol) of potassium permanganate in 4 l of water is added indrops, and it is stirred for 2 hours under reflux. It is cooled to roomtemperature (RT), 50 g of sodium sulfite is added, and it is stirred forone hour at room temperature. Then, it is set at a pH of 1 with 50%sulfuric acid. It is largely concentrated by evaporation in a vacuum,and residual water is azeotropically distilled out by adding ethanol(continuous addition of ethanol). At a water content <1% (KF), another10 l of ethanol is added, and it is stirred for one hour at 40° C.Filtration is done from salt paste, and it is flushed two more timeswith 5 l of isopropanol. The filtrate is evaporated to the dry state ina vacuum.

Yield: 215 g (90% of theory)

Elementary analysis: Cld.: C 18.39 H 0.51 J 64.77 Fnd.: C 18.41 H 0.54 J64.59Production of Triiodotrimesic Acid (D) (Variant E)

250 g (407 mmol) of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzeneis suspended in 2.5 l of water and mixed carefully at 90° C. with 200 mlof 50% sodium hydroxide solution, and it is stirred for 5 hours at 90°C. Then, it is neutralized with concentrated hydrochloric acid (pH=6-7),mixed with 367 g (1.488 mol) of magnesium sulfate, a solution thatconsists of 411 g (2.604 mol) of potassium permanganate in 4 l of wateris added in drops, and it is stirred for 2 hours under reflux. It iscooled to room temperature (RT), 50 g of sodium sulfite is added, and itis stirred for one hour at room temperature. Then, it is set at a pH of1 with 50% sulfuric acid. It is largely concentrated by evaporation in avacuum, and residual water is azeotropically distilled out by addingisopropanol (continuous addition of isopropanol). At a water content <1%(KF), another 10 l of isopropanol is added, and it is stirred for onehour at 40° C. Filtration is done from salt paste, and it is flushed twomore times with 5 l of isopropanol. The filtrate is evaporated to thedry state in a vacuum.

Yield: 214 g (90% of theory)

Elementary analysis: Cld.: C 18.39 H 0.51 J 64.77 Fnd.: C 18.47 H 0.55 J64.71Production of Triiodotrimesic Acid (I) (Variant F)

250 g (407 mmol) of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzeneis suspended in 2.5 l of water and mixed carefully at 90° C. with 200 mlof 50% sodium hydroxide solution, and it is stirred for 5 hours at 90°C. Then, it is neutralized with concentrated hydrochloric acid (pH=6-7),mixed with 367 g (1.488 mol) of magnesium sulfate, a solution thatconsists of 411 g (2.604 mol) of potassium permanganate in 4 l of wateris added in drops, and it is stirred for 2 hours under reflux. It iscooled to room temperature (RT), 50 g of sodium sulfite is added, and itis stirred for one hour at room temperature. Then, it is set at a pH of1 with 50% sulfuric acid. It is largely concentrated by evaporation in avacuum, and residual water is azeotropically distilled off by addingethanol (continuous addition of ethanol). At a water content <1% (KF),another 10 l of ethanol is added, and it is stirred for one hour at 40°C. Filtration is done from salt paste, and it is flushed two more timeswith 5 l of ethanol. The filtrate is evaporated to the dry state in avacuum.

Yield: 213 g (89% of theory)

Elementary analysis: Cld.: C 18.39 H 0.51 J 64.77 Fnd.: C 18.44 H 0.54 J64.66Production of Triiodotrimesic Acid (I) (Variant G)

250 g (407 mmol) of 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzeneis suspended in 2.5 l of water and mixed carefully at 90° C. with 200 mlof 50% sodium hydroxide solution, and it is stirred for 5 hours at 90°C. Then, it is neutralized with concentrated hydrochloric acid (pH=6-7),mixed with 367 g (1.488 mol) of magnesium sulfate, a solution thatconsists of 411 g (2.604 mol) of potassium permanganate in 4 l of wateris added in drops, and it is stirred for 2 hours under reflux. It iscooled to room temperature (RT), 50 g of sodium sulfite is added, and itis stirred for one hour at room temperature. Then, it is set at a pH of1 with 50% sulfuric acid. It is largely concentrated by evaporation in avacuum, and residual water is azeotropically distilled out by addingmethanol (continuous addition of methanol). At a water content <2%(KF-titration), another 10 l of methanol is added, and it is stirred forone hour at 40° C. Filtration is done from salt paste, and it is flushedtwo more times with 5 l of methanol. The filtrate is evaporated to thedry state in a vacuum.

Yield: 213 g (89% of theory)

Elementary analysis: Cld.: C 18.39 H 0.51 J 64.77 Fnd.: C 18.36 H 0.62 J64.72

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The preceding preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the examples, all temperatures are set forthuncorrected in degrees Celsius, and all parts and percentages are byweight, unless otherwise indicated.

The entire disclosure[s] of all applications, patents and publications,cited herein and of corresponding German Application No. 103 32 552.2,filed Jul. 14, 2003, and U.S. Provisional Application Ser. No.60/487,976, filed Jul. 18, 2003, are incorporated by reference herein.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. Process for the production of triiodotrimesic acid, characterized inthat in an oxidation process, triiodomesitylene is reacted withpotassium or sodium permanganate in a mixture that consists of aceticacid anhydride, acetic acid and sulfuric acid at temperatures of 10 to120° C. within 12 to 36 hours, and then the thus obtained intermediateproduct 1,3,5-triiodo-2,4-diacetoxymethylene-6-methylbenzene isisolated, the latter is then treated with a base for 1.5 to 34 hours attemperatures of between 60 and 100° C., then the reaction solution isneutralized and then it is treated with an aqueous potassium or sodiumpermanganate solution at temperatures of 60 to 100° C. within 1 to 24hours.
 2. Process according to claim 1, wherein the reaction to form theintermediate product is performed at 40 to 80° C.
 3. Process accordingto claim 1, wherein the reaction to form the intermediate product isperformed within 15 to 25 hours.
 4. Process according to claim 1,wherein the basic treatment of the intermediate product is performed at80 to 100° C.
 5. Process according to claim 1, wherein the basictreatment of the intermediate product is performed within 3 to 12 hours.6. Process according to claim 1, wherein the oxidation of theintermediate product is performed at 80 to 100° C.
 7. Process accordingto claim 1, wherein the oxidation of the intermediate product isperformed within 2 to 4 hours. 8.1,3,5-Triiodo-2,4-diacetoxymethylene-6-methylbenzene.